Leg ulcerations have long been identified as a serious and debilitating complication of SCD and even the first SCD patient described in North America in 1910 had leg ulcerations. The prevalence varies, being low before 10 years of age, and in genotypes other than SS, and it is influenced by geographical location, with an occurrence as high as 75 percent of SS patients in Jamaica, and 8-10 percent in North America. The etiology of chronic ulcers in SCD and other hemolytic disorders is unknown, mechanical obstruction by dense sickled red cell, increased venous pressure, bacterial infections, abnormal autonomic control with excessive vasoconstriction when in the dependent position, degree of anemia with decrease in oxygen carrying capacity, and in situ thrombosis, have all been proposed as potential contributing factors. Recent studies have reported increased incidence of leg ulcers in patients with pulmonary hypertension. Our group has pioneered the notion of an association between the hemolytic phenotype and leg ulcers. Current treatment options for leg ulcerations, including antibiotics, compression bandages, dressing changes, Unna boots, silver and zinc oxide gauze, skin grafts and maggot therapy rely mostly on bacterial containment, stimulation of granulation formation and decrease of venostasis. Pathological changes in the microcirculation associated with ulceration are not addressed. Nitric oxide metabolism has been the focus of our branch research over the past several years. We know that it mediates essential biological processes, including vasodilatation, wound healing, and angiogenesis and has antimicrobial activity. Moreover, NO has an antiplatelet effect and influences several growth factors involved in endothelial homeostasis.